Targeting multiple COVID variants through the twist in the spike protein

March 19, 2024
Written By:
Derek Smith, U-M College of Engineering

Particles that gum up the keys that the virus uses to enter cells could one day be an effective COVID treatment whenever vaccines and other treatments fall short

Teardrop-shaped particles are arranged in a mosaic pattern. An inset in the upper right corner of the image shows a close up view of one of the particles. Two scale bars reveal that the particles are around 30 nanometers long and 5 nanometers wide.
While vaccines can prevent people from contracting serious cases of COVID-19, the disease can still send some vaccinated people to the hospital, particularly the elderly. These tear-drop shaped particles could prove to be an effective treatment for those individuals still at risk of contracting COVID-19. Image credit: Rui Gao and Xinxin Xu, Jiangnan University.

Teardrop-shaped particles designed to inactivate multiple strains of the SARS-CoV-2 virus could one day complement existing treatments for COVID-19, according to a new study led by researchers at the University of Michigan and Jiangnan University in Wuxi, China.

The COVID mRNA vaccines have been highly effective at preventing severe cases of the disease, but COVID-19 can still hospitalize vaccinated individuals, especially the elderly. New strains also continue to emerge, requiring constant updates to vaccines to maintain their effectiveness.

“Our immune system has to learn about a virus to generate the antibodies to fight back against infection, but by that time it may be too late for some people,” said Nicholas Kotov, the Irving Langmuir Distinguished University Professor of Chemical Sciences and Engineering at U-M and co-corresponding author of the study published in Proceedings of the National Academy of Sciences.

A yellow particle resembles a snow cone or tear drop with many facets, like a gemstone. The pointy end has a drill-like spiral that causes the left edge to bow outward and the tip to curve slightly to the right.
This 3D model of a nanoparticle illustrates the left-handed twist that allows them to easily slot into the grooves in the virus spike protein, the part of the virus that recognizes and attaches to human cells. Because of the particle’s left-handed twist, the virus proteins bind more tightly to the particles than human cells. Image credit: Prashant Kumar, Kotov Lab, University of Michigan

Treatments are essential to help people at risk of severe COVID-19, but there are only a few options on the market today. Pfizer’s Paxlovid antiviral pill has become the go-to treatment after it received emergency use authorization from the Food and Drug Administration, with clinical trials showing hospitalization risk reduced by 89%. However, it may only reduce that risk by 50%, possibly as low as 26%, and the pill might not be appropriate for patients with cardiovascular disease.

“The nanoparticles could help vulnerable people during outbreaks of pandemic virus,” said Liguang Xu, professor of food science and technology at Jiangnan University and co-corresponding author of the study.

The SARS-CoV-2 spike protein—the piece of the virus that both allows it to attack human cells and be attacked by the immune system—is made of building blocks called amino acids, and the sequence of amino acids may change from one strain of the virus to another. Antibodies tend to target a specific amino acid sequence, which is why these changes can enable new strains to evade immunity acquired from prior exposure to other SARS-CoV-2 variants or older versions of the mRNA vaccines.

Instead, the team’s nanoparticles work on the direction and degree of the twist in spike proteins, also known as their chirality.

“The overall structures of coronavirus spike proteins are similar, and the chirality of these spike proteins is the same, so the particles can interact with many coronaviruses,” said Chuanlai Xu, professor of food science and technology who led the work done at Jiangnan University.

The team tested the particles on common cold viruses and the Wuhan-1 and Omicron variants of SARS-CoV-2. They did this by treating mice infected with pseudoviruses that bore coronavirus spike proteins on their surfaces, with different pseudoviruses representing different strains. When the mice inhaled the particles, the treatment cleared 95% of the viruses from their lungs, and they could resist infection for up to three days.

Chirality comes in two directions, left- and right-handed. Coronavirus spike proteins have left-handed twists, so left-handed twists at the nanoparticles’ points fit best.

The leftmost side of a white circular blob (the virus) is covered in gray, teardrop-shaped nanoparticles.
The nanoparticles can attach to a pseudovirus producing the SARS-CoV-2 spike protein. Eventually, the nanoparticles will coat the surface of the virus and make it unable to enter cells. Image credit: Rui Gao and Xinxin Xu, Jiangnan University.

“The matching left-handed twist makes the virus better at binding with the particles than with animal and human cells,” said André Farias de Moura, associate professor of chemistry at the Federal University of São Carlos in Brazil and a co-author of the study. “This makes it more likely that the virus will be captured by the particles before it has a chance to infect cells.”

The researchers still don’t know how quickly the particles are expelled from the body and whether they come with any dangerous side effects in humans, but they hope to learn those details with further study.

The study also included researchers at the Chinese Academy of Medical Sciences and Peking Union Medical College and the Brazilian Center for Research in Energy and Materials.

The research was funded by the National Natural Science Foundation of China, U.S. National Science Foundation, Brazil’s National Council for Scientific and Technological Development, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Program of Tutorial Education of the Brazilian Ministry of Education and the State of São Paulo Research Foundation. Computational resources were provided by the National Laboratory for Scientific Computing and the Cloud@UFSCar.

Kotov is also the Joseph B. and Florence V. Cejka Professor of Engineering and a professor of macromolecular science and engineering.